Cancer therapies are based on the theory that cells with accelerated rates of division and proliferation are predisposed to the development of cancer. Recently, a number of epidemiologic studies have shown consistently that high circulating levels of a potent mitogen, insulin-like growth factor (IGF)-I, are associated with increased risk for several common cancers, including those of the breast, prostate, lung, and colorectum. The level of IGF-binding protein (IGFBP)-3, a major IGF-I-binding protein in serum that, in most situations, suppresses the mitogenic action of IGF-I, is inversely associated with the risk of these cancers.
Functionally, IGF-I not only stimulates cell proliferation but also inhibits apoptosis. The combination of these mitogenic and antiapoptotic effects can have an impact on tumor growth. Besides their direct effect on cancer-related cellular activities, members of the IGF family also interact with a variety of molecules that are involved in cancer development and progression, including the sex steroid hormones, products of tumor suppressor genes, and other growth factors. Furthermore, the expression and production of IGF-I, a peptide hormone that is involved in regulating human growth and development, are influenced by nutrition and physical activity. Experiments to understand the molecular structure and physiologic function of members of the IGF family provide insights into the role of mitogenic growth factors in carcinogenesis. Yu and Rohan, J. Natl. Cancer Inst. 92: 1472-1489, 2000.
IGFs stimulate the proliferation of cultured human breast cancer cells. This stimulation is mediated through the receptor, insulin-like growth factor receptor 1 (IGFR-1), which is a member of the receptor tyrosine kinase family. When activated by its ligands (IGF-I or IGF-II), IGFR1 phosphorylates tyrosine residues on two major substrates, IRS-1 and Shc, which subsequently signal through the Ras/Raf and phosphatidylinositol 3′-kinase/AKT pathways. IGFR1 plays a crucial role in transformation. Cells derived from IGFR1 knockout mice are resistant to transformation by various viral and cellular oncogenes, including SV40 large T antigen and activated ras, whereas fibroblast cells from wild-type mice can be readily transformed by these oncogenes.
There is increasing epidemiological evidence to link elevated plasma IGF-I level with prostate, breast, and colon cancer risk. Breast cancer tissues from patients exhibit higher IGFR1 expression than adjacent normal tissue, suggesting a link between IGFR1 and breast epithelial cell transformation. It has been reported that the transformation capacity of tumor cells is attenuated when IGFR1 is inhibited using an antisense strategy, neutralizing antibody (anti-IR3 or anti-IGF-I) or dominant negative truncation of the receptor. Hailey, J. et al, Molecular Cancer Therapeutics 1: 1349-1353, 2002; Maloney E. K., et al, Cancer Res. 63: 5073-5083, 2003; Burtrum D., et al, Cancer Res., 63: 8912-8921, 2003; Lu et al., J. Biol. Chem. 279: 2856-2865, 2004; Miyamoto et al., Clin. Cancer Res. 11: 3494-3502, 2005; Goya et al., Cancer Research 64: 6252-6258, 2004. A need exists in the art for improved multi-target therapies to treat neoplastic disease and metastatic cancers.